tbuckley/cabot-search huggingface dataset:
NCCN Guidelines Update: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Authors: Deborah M. Stephens
Journal: Journal of the National Comprehensive Cancer Network (2023)

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is characterized by the accumulation of abnormal lymphocytes in the blood, bone marrow, and lymphoid tissues, leading to a weakened immune system and an increased risk of infections for patients. The NCCN Guidelines for CLL/SLL underscore the need for a comprehensive evaluation of multiple factors to determine the most appropriate treatment approach for each patient. For frontline therapy, the selection process should consider the patient’s IGHV status, del(17p)/ TP53 mutation status, age, and comorbidities. In choosing subsequent therapy, prior therapy, comorbidities, and resistance mutations should be considered. With no clear evidence of a functional cure, it is important to enroll patients in clinical trials when available.
NCCN Guidelines for Central Nervous System Cancers: Updates in the Treatment of Adult Patients With Glioma
Authors: Craig M. Horbinski, L. Burt Nabors
Journal: Journal of the National Comprehensive Cancer Network (2023)

In 2021, the WHO revised its classification of central nervous system (CNS) tumors, which has resulted in changes to both the diagnostic and treatment landscapes. At the NCCN 2023 Annual Conference, this tumor board–style presentation featured 4 case studies to demonstrate an evidence-based approach to the treatment of patients with various WHO-defined types of diffuse glioma. The NCCN Guidelines have been updated to reflect the WHO reclassification of CNS tumors and provide treatment recommendations accordingly.
Updates in the Treatment of Metastatic Colorectal Cancer
Authors: Midhun Malla, Katrina S. Pedersen, Aparna R. Parikh
Journal: Journal of the National Comprehensive Cancer Network (2023)

Molecular biomarker testing for all patients with metastatic colorectal cancer (CRC) has become increasingly important because identifying targetable alterations can lead to meaningful clinical benefits. At a minimum, testing should include RAS , BRAF mutational status, microsatellite instability status, HER2 expression, NTRK , and RET mutations. For HER2 -amplified cancer, the NCCN Guidelines offer multiple treatment options, including trastuzumab in combination with tucatinib or pertuzumab, and trastuzumab-deruxtecan. Combination trastuzumab + tucatinib has recently received approval by the FDA for refractory RAS wild-type, HER2-amplified CRC. The addition of bevacizumab to trifluridine/tipiracil treatment has significantly prolonged median overall survival compared with trifluridine/tipiracil alone, regardless of molecular subtypes. KRAS G12C–targeted therapies are on the horizon, with several agents in ongoing studies. Furthermore, bilevel blockade is important when addressing MAP kinase pathway alterations.
Targeted Therapy for Metastatic Non–Small Cell Lung Cancer
Authors: Gregory J. Riely
Journal: Journal of the National Comprehensive Cancer Network (2023)

The use of next-generation tyrosine kinase inhibitors has led to improved progression-free survival for patients with metastatic non–small cell lung cancer (NSCLC) and those with EGFR -mutant and ALK -positive tumors. Newer therapeutics can now target KRAS G12C mutations, EGFR exon 20 insertions, and ERBB2 ( HER2) mutations. Patients with metastatic NSCLC should undergo molecular testing for these mutations as well as for BRAF mutations; MET exon 14 skipping alterations; and ROS1 , RET , and NTRK gene rearrangements (fusions). Novel targeted therapeutics are emerging at a fast pace.
A prospective multicenter study to evaluate the impact of cryotherapy on dysphagia and quality of life in patients with inoperable esophageal cancer
Authors: Toufic Kachaamy, Neil Sharma, Tilak Shah, Sonmoon Mohapatra, Kimberly Pollard, Christina Zelt, Elaine Jewett, Rigoberto Garcia, Rachel Munsey, Saurabh Gupta, Mariajose Rojas-DeLeon, Digant Gupta, Vivek Kaul, Rahul Pannala, Pankaj Vashi
Journal: Endoscopy (2023)

Dysphagia palliation in inoperable esophageal cancer continues to be a challenge. Self-expandable metal stents have been the mainstay of endoscopic palliation but have a significant risk of adverse events (AEs). Liquid nitrogen spray cryotherapy is an established modality that can be used with systemic therapy. This study reports the outcomes of cryotherapy, including dysphagia and quality of life (QoL), in patients receiving systemic therapy.This was a prospective multicenter cohort study of adults with inoperable esophageal cancer who underwent cryotherapy. QoL and dysphagia scores before and after cryotherapy were compared.55 patients received 175 cryotherapy procedures. After a mean of 3.2 cryotherapy sessions, mean QoL improved from 34.9 at baseline to 29.0 at last follow-up (P < 0.001) and mean dysphagia improved from 1.9 to 1.3 (P = 0.004). Patients receiving more intensive cryotherapy (≥ 2 treatments within 3 weeks) showed a significantly greater improvement in dysphagia compared with those not receiving intensive therapy (1.2 vs. 0.2 points; P = 0.003). Overall, 13 patients (23.6 %) received another intervention (1 botulinum toxin injection, 2 stent, 3 radiation, 7 dilation) for dysphagia palliation. Within the 30-day post-procedure period, there were three non-cryotherapy-related grade ≥ 3 AEs (all deaths). The median overall survival was 16.4 months.In patients with inoperable esophageal cancer receiving concurrent systemic therapy, adding liquid nitrogen spray cryotherapy was safe and associated with improvement in dysphagia and QoL without causing reflux. More intensive treatment showed a greater improvement in dysphagia and should be considered as the preferred approach.
Limited plasticity of monocyte fate and function associated with epigenetic scripting at the level of progenitors
Authors: Catherine Rhee, Elizabeth W. Scadden, Lai Ping Wong, Giulia Schiroli, Michael C. Mazzola, Phillip L. Chea, Hiroki Kato, Friedrich F. Hoyer, Meeta Mistry, Bum-Kyu Lee, Jonghwan Kim, Matthias Nahrendorf, Michael K. Mansour, David B. Sykes, Ruslan I. Sadreyev, David T. Scadden
Journal: Blood (2023)

Myeloid cell heterogeneity is known, but whether it is cell-intrinsic or environmentally-directed remains unclear. Here, an inducible/reversible system pausing myeloid differentiation allowed the definition of clone-specific functions that clustered monocytes into subsets with distinctive molecular features. These subsets were orthogonal to the classical/nonclassical categorization and had inherent, restricted characteristics that did not shift under homeostasis, after irradiation, or with infectious stress. Rather, their functional fate was constrained by chromatin accessibility established at or before the granulocyte-monocyte or monocyte-dendritic progenitor level. Subsets of primary monocytes had differential ability to control distinct infectious agents in vivo. Therefore, monocytes are a heterogeneous population of functionally restricted subtypes defined by the epigenome of their progenitors that are differentially selected by physiologic challenges with limited plasticity to transition from one subset to another.
Haplodeficiency of the 9p21 tumor suppressor locus causes myeloid disorders driven by the bone marrow microenvironment
Authors: Jue Feng, Pei-Feng Hsu, Eduardo Esteva, Rossella Labella, Yueyang Wang, Alireza Khodadadi-Jamayran, Joseph Pucella, Cynthia Z. Liu, Arnaldo A. Arbini, Aristotelis Tsirigos, Stavroula Kousteni, Boris Reizis
Journal: Blood (2023)

The chromosome 9p21 locus comprises several tumor suppressor genes including MTAP, CDKN2A, and CDKN2B, and its homo- or heterozygous deletion is associated with reduced survival in multiple cancer types. We report that mice with germ line monoallelic deletion or induced biallelic deletion of the 9p21-syntenic locus (9p21s) developed a fatal myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN)-like disease associated with aberrant trabecular bone formation and/or fibrosis in the bone marrow (BM). Reciprocal BM transfers and conditional targeting of 9p21s suggested that the disease originates in the BM stroma. Single-cell analysis of 9p21s-deficient BM stroma revealed the expansion of chondrocyte and osteogenic precursors, reflected in increased osteogenic differentiation in vitro. It also showed reduced expression of factors maintaining hematopoietic stem/progenitor cells, including Cxcl12. Accordingly, 9p21s-deficient mice showed reduced levels of circulating Cxcl12 and concomitant upregulation of the profibrotic chemokine Cxcl13 and the osteogenesis- and fibrosis-related multifunctional glycoprotein osteopontin/Spp1. Our study highlights the potential of mutations in the BM microenvironment to drive MDS/MPN-like disease.
Efficacy and safety results by age in monarchE: Adjuvant abemaciclib combined with endocrine therapy (ET) in patients with HR+, HER2-, node-positive, high-risk early breast cancer (EBC).
Authors: Erika P. Hamilton, Jee Hyun Kim, Natalja Eigeliene, Dimitrios Mavroudis, Dragos Mircea Median, Heloisa Marconato, Serhii Shevnia, Ozgur Ozyilkan, Juan Manuel Puig, Catherine M. Shannon, Maria Munoz, Belén San Antonio, Ran Wei, Joyce O'Shaughnessy, Stephen R. D. Johnston, Valentina Guarneri
Journal: Journal of Clinical Oncology (2023)

501 Background: Adjuvant abemaciclib (a CDK4 &amp; 6 inhibitor) combined with ET demonstrated a sustained benefit in invasive disease-free survival (IDFS) and a tolerable safety profile in patients (pts) with HR+, HER2-, node-positive, high-risk EBC. Almost half of the newly diagnosed breast cancers occur in women older than 65 years. Older pts often have a higher incidence of comorbidities and increased risk for toxicities. Here, we report efficacy and safety by age subgroups in monarchE to help guide management of older pts receiving adjuvant abemaciclib. Methods: Pts were randomized (1:1) to receive ET for up to 10 years +/- abemaciclib for 2 years (study treatment period). Efficacy in IDFS and distant relapse-free survival (DRFS) was assessed in the intent-to-treat population by the pre-specified age groups of &lt;65 and ≥65 years, with hazard ratios (HR) estimated using unstratified Cox proportional hazard model within each subgroup. Safety was evaluated among older pts (≥65 years) in two subgroups; 65-74 and ≥75 years. Results: In monarchE (NCT03155997), 4787 pts (84.9%) were aged &lt;65 years and 850 pts (15.1%) were ≥65 years. At median follow-up of 42 months, a numerically favorable IDFS effect was observed in both the &lt;65 (270 vs 414 events; HR = 0.646, 95% CI: 0.554, 0.753) and ≥65 (66 vs 85 events; HR = 0.767, 95% CI: 0.556, 1.059) groups for abemaciclib + ET vs ET alone. Similar findings were observed in DRFS. Older pts (≥65 years) had ~5% higher incidence of grade ≥3 adverse events (AEs) than younger pts, mainly diarrhea and fatigue. Neutropenia was not increased among older pts and similarly, venous thromboembolic events occurred at similar rates (≥65 years, 3.0%; &lt;65 years, 2.5%). Serious AEs (SAEs) and treatment discontinuations due to AEs were more common in older pts. Older pts required more dose reductions to manage AEs. Conclusions: In pts with high-risk EBC, adjuvant abemaciclib + ET showed treatment benefit across age subgroups with a manageable safety profile. Older pts did have higher rates of AEs and discontinuations, especially those older than 75 years, suggesting that more frequent surveillance with early intervention may be key to the management of these pts. Clinical trial information: NCT03155997 . [Table: see text]
Highly resilient and fatigue-resistant poly(4-methyl-ε-caprolactone) porous scaffold fabricated via thiol-yne photo-crosslinking/salt-templating for soft tissue regeneration
Authors: Zhaochuang Wang, Wenhao Zhang, Guo Bai, Qiaohui Lu, Xiaoyu Li, Yan Zhou, Chi Yang, Yan Xiao, Meidong Lang
Journal: Bioactive Materials (2023)

Elastomeric scaffolds, individually customized to mimic the structural and mechanical properties of natural tissues have been used for tissue regeneration. In this regard, polyester elastic scaffolds with tunable mechanical properties and exceptional biological properties have been reported to provide mechanical support and structural integrity for tissue repair. Herein, poly(4-methyl-ε-caprolactone) (PMCL) was first double-terminated by alkynylation (PMCL-DY) as a liquid precursor at room temperature. Subsequently, three-dimensional porous scaffolds with custom shapes were fabricated from PMCL-DY via thiol-yne photocrosslinking using a practical salt template method. By manipulating the Mn of the precursor, the modulus of compression of the scaffold was easily adjusted. As evidenced by the complete recovery from 90% compression, the rapid recovery rate of >500 mm min-1, the extremely low energy loss coefficient of <0.1, and the superior fatigue resistance, the PMCL20-DY porous scaffold was confirmed to harbor excellent elastic properties. In addition, the high resilience of the scaffold was confirmed to endow it with a minimally invasive application potential. In vitro testing revealed that the 3D porous scaffold was biocompatible with rat bone marrow stromal cells (BMSCs), inducing BMSCs to differentiate into chondrogenic cells. In addition, the elastic porous scaffold demonstrated good regenerative efficiency in a 12-week rabbit cartilage defect model. Thus, the novel polyester scaffold with adaptable mechanical properties may have extensive applications in soft tissue regeneration.
Abstract IA004: Metabolic mechanisms of prostate cancer progression that feed nuclear receptors
Authors: Nima Sharifi
Journal: Cancer Research (2023)

Abstract The androgen axis is central to prostate cancer physiology and therapy. Androgens are gonadal and extragonadal in origin, both of which stimulate the androgen receptor (AR). The use of medical castration (ADT), adrenal androgen ablation (i.e., abiraterone) and potent AR antagonists (i.e., enzalutamide, apalutamide, darolutamide), has yielded complex clinical states of prostate cancer, including disease states that are resistant to multiple forms of hormonal therapy. One of the major questions that arises is whether men can be identified who will benefit from earlier intensive hormonal therapy. Another question is whether alternative hormonal treatment strategies can be used to address resistance to the current generation of hormonal therapies. We propose that identification of steroid metabolic dependencies is part of the answer to both of these questions. Approximately half of men with prostate cancer inherit an activating missense in the first and rate-limiting enzyme that converts extragonadal precursor steroids to dihydrotestosterone (DHT). The “adrenal-permissive” HSD3B1(1245C) allele encodes for a 3β-hydroxysteroid dehydrogenase-1 (3βHSD1) enzyme that increases tumor DHT synthesis from adrenal DHEA. Heterozygous or homozygous HSD3B1(1245C) inheritance confers poor outcomes after ADT. Furthermore, men with HSD3B1(1245C) inheritance and castration-resistant prostate cancer (CRPC) treated with abiraterone or enzalutamide still have poorer outcomes. Together, these data suggest that directly targeting this metabolic lesion is necessary for optimal therapy in these men. We recently discovered that phosphorylation of the 3βHSD1 tyrosine 344 by the BMX kinase is necessary for androgen biosynthesis and CRPC in xenograft models. These findings have led to the launch of the Maverick clinical trial in the Prostate Cancer Clinical Trials Consortium (PCCTC) that combines abiraterone plus BMX inhibition with abivertinib in men with CRPC. In sum, this accumulating body of evidence suggests that steroid metabolic dependencies should be considered as an essential part of cancer metabolism, particularly in the context of developmental therapeutics for prostate cancer. Citation Format: Nima Sharifi. Metabolic mechanisms of prostate cancer progression that feed nuclear receptors [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr IA004.
Abstract A005: Androgen receptor variants mRNA absolute quantification in prostate cancer cell models
Authors: Gabrianne Larson, Zoi Sychev, Stephen Plymate, Eva Corey, Justin M. Drake
Journal: Cancer Research (2023)

Abstract Background: Patients treated with Androgen Deprivation Therapy (ADT) have been shown to increase the expression of constitutively active Androgen Receptor (AR) splice variants (AR-Vs). These splice variants lack the ligand binding domain at the C-terminus of AR, required for binding to antiandrogen therapies. AR-V7 has also been correlated to the development and progression of castration resistant prostate cancer (CRPC). As not all circulating tumor cells (CTCs) contain AR-V7, we hypothesized that other AR-Vs are involved in the mechanism of resistance to ADT commonly seen in CRPC. To test this, we developed an mRNA quantitative assay targeting AR-Vs and then correlated our results with a targeted mass spectrometry (MS) based protein assay. This work will provide a feasible quantification of AR-V transcripts and that may provide a stratification for predicted responses to ADT treatment in patients that could be useful to clinicians. Methods: The absolute copy number of total AR, AR-V2, AR-V7, AR-V12, and AR-V23 were determined in eight different PCa cell lines and 48 patient derived xenografts (PDXs) using qRT-PCR assays. We performed siRNA targeting of these variants to evaluate primer specificity by evaluating knockdown efficiencies. These results will be correlated to targeted MS quantification of AR-Vs in each cell model. Results: We found that the most highly expressed variants in PCa cell lines were AR-V7 and AR-V12. In the LuCaP PDX model, AR-V12 was shown to have the highest expression of the AR-Vs tested. Specificity of AR-V knockdown was tested using AD-1 (which only expresses the full- length AR transcript) and R1-D567 (which only expresses AR-V567es, an AR-V12-like variant) cell lines. Conclusions: We were able to determine the landscape of AR-V mRNA expression in eight PCa cell lines and in 48 PDX tumor samples. This data will be correlated to protein expression currently being analyzed using a targeted MS method developed in our lab. Our work will be useful to help clinicians stratify PCa patients based on their AR-V expression profiles. This will establish a prognostic biomarker program that measures AR-V proteins in real time from clinical biopsy tissues, circulating tumor cells, or exosomes and informs the clinician on which course of treatment may be effective for each patient. Establishing a CRPC biomarker other than AR-V7 that can help explain the AR-V7 negative CRPC patients could eventually improve clinical application and predictive treatment outcomes. Citation Format: Gabrianne Larson, Zoi Sychev, Stephen Plymate, Eva Corey, Justin M. Drake. Androgen receptor variants mRNA absolute quantification in prostate cancer cell models [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A005.
Genetics of hair graying with age
Authors: Sifan Wang, Yuanbo Kang, Fei Qi, Hongzhong Jin
Journal: Ageing Research Reviews (2023)

Hair graying is an early and obvious phenotypic and physiological trait with age in humans. Several recent advances in molecular biology and genetics have increased our understanding of the mechanisms of hair graying, which elucidate genes related to the synthesis, transport, and distribution of melanin in hair follicles, as well as genes regulating these processes above. Therefore, we review these advances and examine the trends in the genetic aspects of hair graying from enrichment theory, Genome-Wide association studies, whole exome sequencing, gene expression studies, and animal models for hair graying with age, aiming to overview the changes in hair graying at the genetic level and establish the foundation for future research. Meanwhile, by summarizing the genetics, it's of great value to explore the possible mechanism, treatment, or even prevention of hair graying with age.
Increasing numbers and complexity of Staphylococcus aureus bloodstream infection—14 years of prospective evaluation at a German tertiary care centre with multi-centre validation of findings
Authors: Philipp Mathé, Siri Göpel, Daniel Hornuss, David Tobys, Nadja Käding, Simone Eisenbeis, Britta Kohlmorgen, Janina Trauth, Hanna Gölz, Sarah V. Walker, Alexander Mischnik, Silke Peter, Florian Hölzl, Anna M. Rohde, Michael Behnke, Moritz Fritzenwanker, Georg Häcker, Benedict Steffens, Maria Vehreschild, Evelyn Kramme, Jane Falgenhauer, Gabriele Peyerl-Hoffmann, Harald Seifert, Jan Rupp, Petra Gastmeier, Can Imirzalioglu, Evelina Tacconelli, Winfried Kern, Siegbert Rieg, Barisch Bader, Yannic Blum, Michael Buhl, Chiara Cattaneo, Ariane Gertraud Dinkelacker, Beryl Primerose Gladstone, Matthias Kleipaß, Dana Lenke, Sara Christina Olawumi-Hurter, Luis Alberto Peña Diaz, Georg Pilarski, Susanna Proske, Norbert Thoma
Journal: Clinical Microbiology and Infection (2023)
Air Pollution and Lung Cancer: A Review by International Association for the Study of Lung Cancer Early Detection and Screening Committee
Authors: Christine D. Berg, Joan H. Schiller, Paolo Boffetta, Jing Cai, Casey Connolly, Anna Kerpel-Fronius, Andrea Borondy Kitts, David C.L. Lam, Anant Mohan, Renelle Myers, Tejas Suri, Martin C. Tammemagi, Dawei Yang, Stephen Lam
Journal: Journal of Thoracic Oncology (2023)
Glutaredoxin 1 regulates cholesterol metabolism and gallstone formation by influencing protein S-glutathionylation
Authors: Yan Xia, Ying Xu, Qinhui Liu, Jinhang Zhang, Zijing Zhang, Qingyi Jia, Qin Tang, Xiandan Jing, Jiahui Li, Jiahao Chen, Yimin Xiong, Yanping Li, Jinhan He
Journal: Metabolism (2023)
Increased expression of sodium-glucose cotransporter 2 and O-GlcNAcylation in hepatocytes drives non-alcoholic steatohepatitis
Authors: Hye Jin Chun, Eun Ran Kim, Minyoung Lee, Da Hyun Choi, Soo Hyun Kim, Eugene Shin, Jin-Hong Kim, Jin Won Cho, Dai Hoon Han, Bong-Soo Cha, Yong-ho Lee
Journal: Metabolism (2023)
Oral Contraceptives and the Risk of Breast Cancer
Authors: Polly A. Marchbanks, Jill A. McDonald, Hoyt G. Wilson, Suzanne G. Folger, Michele G. Mandel, Janet R. Daling, Leslie Bernstein, Kathleen E. Malone, Giske Ursin, Brian L. Strom, Sandra A. Norman, Phyllis A. Wingo, Ronald T. Burkman, Jesse A. Berlin, Michael S. Simon, Robert Spirtas, Linda K. Weiss
Journal: New England Journal of Medicine (2002)

It is uncertain whether the use of an oral contraceptive increases the risk of breast cancer later in life, when the incidence of breast cancer is increased. We conducted a population-based, case–control study to determine the risk of breast cancer among former and current users of oral contraceptives.